Botulinum Toxin

Botulinum toxin (BTX) is naturally occurring substance that is lethal in large doses. Several different strains have been identified (A-F) but only BTX A and B have been found to have therapeutic benefit. In the 1950s researchers found that by injecting overactive muscles with minute quantities of BTX-A they could decrease muscle activity by blocking the release of acetylcholine from the neuron (Mukherjee 2015). BTX-A does this by interfering with SNAP-25 protein. This prevents fusion of the acetylcholine containing vesicles with the nerve terminal membrane, thus preventing the release of acetylcholine into the synaptic cleft and the resultant contraction of the muscle fibers. BTX-B does this similiarly by interfering with synaptin. The effect dissipates after three to six months due to collateral sprouting of new nerve terminals and the eventual full recovery of the original nerve from the effects of the toxin.

There is level 1 evidence supporting the use of type A (BTX-A) and type B (BTX-B) in relieving focal muscle spasticity in a variety of etiologies, most notably stroke and acquired brain injury (SREBR 2016; ERABI 2016). In addition, there are several treatment guidelines and other information available for assisting the clinician with dosing and medication administration decisions (Brin 1997a; Brin 1997b; Gormley Jr. et al. 1997; O’Brien 1997; Ward 2002; Francisco 2004). The recommendation for the use of BTX for relieving focal muscle spasticity in individuals with SCI (Brin 1997b; Kirshblum 1999; Fried & Fried 2003) “is independent of the etiology of the spasticity, depending rather on the presence of an increase in muscle tone that interferes with function” (Brin 1997b). The advantages for its use include the ability to achieve a focal response, a relative ease of administration and avoiding the sedation common with other pharmacological alternatives (Fried & Fried 2003). In spite of this information, there continue to be relatively few studies directed specifically at the SCI population. The successful employment of botulinum neurotoxin to overcome bladder detrusor-sphincter dyssynergia in people with SCI is addressed separately in the SCIRE bladder chapter.

Discussion

Richardson et al. (1997) employed EMG-guided BTX-A injections, to treat several wrist and hand muscles in a single chronic SCI subject. Spasticity was reduced as assessed by the Ashworth Scale and range of motion was increased with these measures maintained over the testing period to 12 weeks. Using the same technique, Al-Khodairy et al. (1998) conducted a two-year follow-up study of a chronic incomplete paraplegic male with similar results augmented by the Spasm Frequency Score and reports of markedly reduced pain due to spasticity, less difficulty with activities of daily living, better sitting tolerance and fewer sleep disturbances. The final treatment delivered in this series (i.e., eighth over two-year period) was without effect leaving the possibility of drug tolerance but this was not confirmed.

In a subsequent, EMG-guided BTX-A injection study of RCT design (Richardson et al. 2000) MAS scores demonstrated reduced spasticity across the appropriate joints when tested at three, six, nine and 12 months with both active treatment and placebo, although there was a significantly greater reduction with BTX-A (p=0.02). Despite the RCT design and the use of a validated spasticity outcome measure, the conclusions must be cautiously interpreted with respect to BTX-A use in SCI, given that only six of 52 subjects had spasticity of confirmed spinal cord origin.

Limited SCI specific evidence of BTX-A benefits is provided by Hecht et al. (2008). They studied a case series of 19 individuals with chronic hereditary spastic paraplegia and reported Ashworth improvements of at least one point (one patient was not scored). 11 of the 19 patients perceived a concurrent improvement in activities of daily living and continued treatment.

In an open label study of 15 individuals with AIS-D SCI, Bernuz et. al. (2012) found significant decreased peak torque in the quardriceps after treatment with 200 units of BTX-A in the form of Botox® into the rectus femoris (RF). Individuals also demonstrated faster walking speeds, improvements in stride length and better performance on stairs post treatment. Individuals also reported improved comfort. There was no change in performance in the 6-minute Walk Test. The authors concluded that BTX-A injection into the RF muscle in incomplete SCI patients led to improvements in impairments, functional aspects of gait, and discomfort that is related to the delay and reduction of RF spasticity in mid-swing.

Spiegl et al. (2014) examined nine male patients with paraplegia and severe spasticity, in an open-label prospective desisgn study. Eight had complete, AIS-A injuries and one was AIS-C. All subjects had not responded to oral therapies and physiotherapy adequately. They were evaluated in a pre-post fashion. They received up to 2000 units (range 800-2000 units) of BTX-A in various muscle groups in the lower extremities. Descriptive analysis showed that six of nine patients reported being very satisfied with the results and showed an average reduction in the Ashworth’s score of 1.9. All those very satisfied with treatment had a post treatment Ashworth’s score of less than two. The one study subject with incomplete, AIS-C paraplegia suffered a decline in mobility following treatment. They concluded that botulinum toxin could be a very promising treatment for spasticity in SCI and that further studies were needed.

Conclusions

There is level 1b evidence (from one RCT, two pre-post studies, and one case series; Richardson et al. 2000; Spiegl 2014; Bernuz et al. 2012; Hecht et al. 2008) that botulinum toxin type A improves focal muscle spasticity in SCI. It is important to note the RCT included just six of 52 subjects with spasticity of confirmed spinal cord origin.

Botulinum neurotoxin may improve focal muscle spasticity in people with SCI.